biweekly versus triweekly raltitrexed with oxaliplatin (with or without bevacizumab) in first-line metastatic colorectal cancer

Conditions: Metastatic Colorectal Cancer

Summary: raltitrexed is a potent thymidylate synthase (ts) inhibitor. conversely to 5-fluorouracil (5fu), raltitrexed can be administered safely in patients with cardiovascular disease, as well as in patients with dihydropyrimidine dehydrogenase deficit. since raltitrexed is administered in 15-minutes infusion, complications related to continuous infusion can be avoided, and it becomes a potential good candidate for locoregional treatments as hepatic intra-arterial or intra-peritoneal infusion. despite these potential benefits over 5fu, clinical trials failed in their temptation to replace the 5fu in colorectal cancer patients, mainly due to raltitrexed toxicity at 3mg/m2 every 3 weeks. oxaliplatin has demonstrated a synergic effect when combined with ts inhibitors, and its association with raltitrexed was evaluated at 130mg/m2 of oxaliplatin and 3mg/m2 of raltitrexed, every 3 weeks. actually, one of the first-line standard regimens in metastatic colorectal cancer patients is the biweekly folfox (85mg/m2 of oxaliplatin, and infusional 5fu) plus bevacizumab regimen, since a significant progression-free survival (pfs) benefit was observed over folfox plus placebo. biweekly administration of raltitrexed at 2mg/m2 demonstrated a favorable toxicity profile even in patients aged \>65 years. besides, the association of raltitrexed, oxaliplatin and bevacizumab seems safe. then, the investigators decided to perform a randomized pharmacokinetic comparative study between biweekly tomox (raltitrexed 2 mg/m2 and oxaliplatin 85mg/m2) and triweekly tomox (raltitrexed 3 mg/m2 and oxaliplatin 130mg/m2) regimens in metastatic colorectal cancer patients, in a "ping-pong" crossover strategy to reduce the intra-individual variability. bevacizumab was allowed at the dose of 5mg/kg or 7.5mg/kg, in biweekly and triweekly schedules, respectively. the secondary end-points were, objective response rate evaluated by recist 1.1 criteria, pfs, overall survival (os), toxicity, and the comparison of toxicity between two arms for the first 2 cycles.


Eligibility criteria:
inclusion criteria: * performance status (ecog-ps) of 0 or 1 * patient with histologically proven colorectal cancer with distant metastases * measurable disease by response evaluation criteria in solid tumors (recist) version 1.1 * life expectancy \> 12 months * signed written informed consent exclusion criteria: * prior chemotherapy at metastatic stage * presence of brain or meningeal metastases * other malignancies in the past 5 years with the exception of adequately treated carcinoma in situ of the cervix and squamous or basal cell carcinoma of the skin * preexisting peripheral neuropathy * known hypersensitivity to any component of the study treatment * any psychiatric condition compromising the understanding of information or conduct of the study * pregnancy, breast-feeding or absence of adequate contraception for fertile patients * patient under guardianship, curator or under the protection of justice

Keywords: colorectal cancer raltitrexed oxaliplatin bevacizumab biweekly triweekly